Transcript CITRIC ACID CYCLE- discovered by Sir Hans Krebs in 19(1900

CITRIC ACID CYCLE- discovered by Sir Hans
Krebs in 1953. He was awarded Nobel Prize in
Medicine
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The citric acid cycle (also known as the
tricarboxylic acid cycle, the TCA cycle, or the
Krebs cycle) is a series of chemical reactions of
central importance in all living cells that utilize
oxygen as part of cellular respiration.
In aerobic organisms, the citric acid cycle is part
of a metabolic pathway involved in the chemical
conversion of carbohydrates, fats and proteins
into carbon dioxide and water to generate a form
of usable energy.
It is the second of three metabolic pathways that
are involved in fuel molecule catabolism and ATP
production, the other two being glycolysis and
oxidative phosphorylation.
The citric acid cycle also provides precursors for
many compounds such as certain amino acids,
and some of its reactions are therefore important
even in cells performing fermentation.
ACETYL-CoA (Acetyl Coenzyme A,
ACoA)
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Catabolism of carbohydrates, fatty acids, amino
acids releases energy from ACoA
During glycolysis, glucose is converted to
pyruvate which is converted to ACoA by a group
of enzymes known as pyruvate dehydrogenase
complex
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NADH is produced during those process
In TCA two carbon atoms of the acetylCoenzyme A are ultimately oxidized to CO2
ACoA is a carrier of acyl groups and the
catalyzed steps of TCA occurs in the
mitochondria.
CITRIC ACID CYCLE
REACTIONS OF THE CITRIC ACID CYCLE
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CITRIC SYNTHASE catalyses the condensation
of ACoA with oxaloacetate to form citrate. The
reaction is reversible, but is a main regulatory
point. A low NAD+/NADH ratio and succinylCoA inhibits its activity
ACONITASE reversibly catalyses the conversion
of citrate to isocitrate
ISOCITRATE DEHYDROGENASE oxidatively
decarboxylates isocitrate to α-ketoglutarate
(2-oxyglutarate). In this process NAD+ s
reduced to NADH and CO2 is released.
Isocitrate dehydrogenase is inhibited by ATP
and NADH and activated by ADP and NAD+
REACTIONS contd.
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α-KETOGLUTARATE DEHYDROGENASE produces
succinyl- CoA from α-ketogluturate and coenzyme A.
Another NAD+ is reduced to NADH and CO2 is
released. Both NADH and succinyl-CoA inhibit the
enzyme complex, 2-oxygluturate dehyrogenase
complex
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SUCCINYL-CoA SYNTHETASE converts succinyl-CoA to
succinate. GDP (glyceralaldehyde di-phosphate) is
converted to GTP during this step. This is the only step
in TCA (citric acid cycle) that involves substrate-level
phosphoyrlation to directly produce a high energy
phosphate bond.
REACTIONS contd.
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SUUCINATE DEHYDROGENASE SYNTHETASE oxidizes
succinate to fumarate. This enzyme is membrane
bound in the mitochondria and transfers two H+ to
FAD to form FADH2. It is inhibited by oxaloacetate.
FUMARATE HYDRATASE (fumarase) reversebly
hydrates fumarate to form malate.
MALATE DEHYDRGENASE forms oxaloacetate and
one more FADH from malate to complete the cycle
Hence, one cycle produces 1 GTP (step 5), 3 NADH’s
(steps 3 ,4, and 8) and 1FADH2 (step 6).
SUMMARY OF THE REACTIONS
The sum of all reactions in the citric acid cycle is:
Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 3 H2O
→
CoA-SH + 3 NADH + H+ + FADH2 + GTP + 2
CO2 + 3 H+
Two carbons are oxidized to CO2, and the energy
from these reactions is stored in GTP , NADH
and FADH2. NADH and FADH2 are coenzymes
(molecules that enable or enhance enzymes)
that store energy and are utilized in oxidative
phosphorylation.
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SIMPLIFIED VIEW OF THE
PROCESS
The
process begins with the oxidation of pyruvate, producing one
CO2, and one acetyl-CoA.
Acetyl-CoA reacts with the four carbon carboxylic acid, oxaloacetate-to form the six carbon carboxylic acid, citrate.
Through a series of reactions citrate is converted back to
oxaloacetate. This cycle produces 2 CO2 and consumes 3 NAD+,
producing 3 NADH and 3 H+.
It consumes 3 H2O and consumes one FAD, producing one FADH+.
1st turn end= 1 ATP, 3 NADH, 1 FADH2, 2 CO2
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Since there are two molecules of Pyruvic acid to deal with, the cycle
turns once more.
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The complete end result= 2 ATP, 6 NADH, 2 FADH2, 4 CO2
REGULATION
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Many of the enzymes in the TCA cycle are regulated by
negative feedback from ATP when the energy charge of
the cell is high.
Such enzymes include the pyruvate dehydrogenase
complex that synthesises the acetyl-CoA needed for the
first reaction of the TCA cycle.
Also the enzymes citrate synthase, isocitrate
dehydrogenase and alpha-ketoglutarate dehydrogenase,
that regulate the first three steps of the TCA cycle, are
inhibited by high concentrations of ATP.
This regulation ensures that the TCA cycle will not
oxidise excessive amounts of pyruvate and acetyl-CoA
when ATP in the cell is plentiful. This type of negative
regulation by ATP is by an allosteric mechanism
REGULATION contd.
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Several enzymes are also negatively
regulated when the level of reducing
equivalents in a cell are high (high ratio of
NADH/NAD+).
This mechanism for regulation is due to
substrate inhibition by NADH of the
enzymes that use NAD+ as a substrate.
This includes both the entry point
enzymes pyruvate dehydrogenase and
citrate synthase.
ENERGETICS OF TCA
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The overall consumption of one molecule of acetylCoA in the TCA is a spontaneous, exergonic process
(having overall negative free energy change) ; ΔGo’
= -60 kJ mol-1.
The rate of utilization of the ACoA in the cycle
depends on the energy status within the
mitochondria.
Under conditions of high energy, the concentrations
of NADH and ATP are high, and those of NAD+ and
FADH2 are low.
The reoxidation of NADH and FADH2 occurs in the
electron transport chain and is necessary for he
cycle to continue.
IMPORTANT FACTS
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Many of the intermediates of the citric
acid cycle are used in in the synthesis
of other biomolecules
Many biomolecules feed into the citric
acid cycle
Thus, the TCA is considered to be
amphibolic
OVERALL CHEMICAL
REACTIONS DURING ONE TURN
OF TCA
The overall reactions are the
complete oxidation of one
molecule of ACoA, the release of
two molecules of CO2, the
reduction of three molecules of
NAD+ and one FAD, and the
phosphorylation of one
molecule of GDP.